2.0 LITERATURE REVIEW
Propofol
Propofol is mostly used as intravenous anesthetic agent. It induces sedation by inhibiting GABA neurotransmitter, slowing chloride channel closing time substantially lead to hyperpolarization of cell membrane (Propofol mechanism of action, n.d.). Propofol has large volume of distribution and high total body clearance. The amount of propofol excreted via liver is very high however very little amount of unchanged propofol detected in urine. Since the hepatic clearance of propofol is high it indicates hepatic clearance was limited by blood flow. However findings show total body clearance of propofol is greater than hepatic blood flow suggesting involvement of extrahepatic clearance (Hiraoka, et al., 2005).
Small Intestine
Small intestine is a site where absorption of nutrients and water and expels of waste materials that are ingested through oral route. Along the gastrointestinal tract, there are mucosal cells that secretes enzyme that allow absorption nutrients and water by passage of their digested end products from lumen of gastrointestinal tract into blood and lymph (The Digestive System, n.d.). Furthermore, mucosal cells become major route of entry of xenobiotics such as drug to get into the body (Lin, Chiba & Baillie, 1999). Moreover, small intestine able to metabolize compounds by phase I and phase II metabolism pathways (Lin, et al., 1999) make it become the site of first pass effect of orally ingested compounds.
The absorption and metabolism in the intestine mainly depends on physiochemical properties of xenobiotic molecules, anatomy and physiology of intestine, permeability of compounds, protein binding as well as enzymatic activity in the intestine (Thorn, 2012). Both reactions in small intestine substantially contributes to first pass effect of compounds taken from oral route.
Small intestine is made up of three parts which are duodenum, jejunum and ileum. It has a large surface area provided by extensive folding of epithelial cells and villi that allow digestion and absorption of nutrients and drugs. Generally, the three parts of small intestine has similar histological patterns which made up of mucosa, submucosa, muscle layers and serosa. Enterocytes are absorptive cells that located on mucosal lining. Enterocytes are responsible to absorb nutrients from intestinal lumen across the epithelium to diffuse into systemic circulation. Mechanisms of absorption in intestines is passive mediated by paracellular and transcellular transport (Meunier, Bourrie, Berger & Fabre, 1995; Yee, 1997). Paracellular transport allow passage of nutrients and drugs across tight junction between epithelial cells of intestines. Transcellular mechanism transports compound across the plasma membrane of the epithelial cells (Bowen, 2006). However, certain drugs that are lipophilic utilizes carrier-mediated transport to across the cell membrane (Yee, 1995; Dobson & Kell, 2008). Mucosal blood flow is one of the factors that affect absorption of molecules into systemic circulation. Small intestine is mainly supplied by superior mesenteric artery (Lin, et al., 1999). During absorption, the blood flow increases significantly and returns to baseline once the compound passes that region.
Small intestine play an important role as first line defense against orally ingested xenobiotics. Small intestine able to metabolize drugs or any foreign toxic compounds and limits their bioavailability. The metabolic reactions that occur such as phase I and phase II metabolism. Phase I metabolism is mainly depending on cytochrome P-450 superfamily (Lin et al., 1999). The most common reaction in phase I metabolism is oxidation. Cytochrome P-450 enzyme act as major catalyst for drug oxidation allow most drugs to be more hydrophilic compound before being excreted from the body (Gavhane & Yadav, 2012). This metabolism basically help lower high dosage of drugs or entrance of toxic compounds into systemic circulation. Generally, CYP3A4 is the most abundant enzyme in small intestine and liver that catalyzes biotransformation of many drugs and toxic compounds (Gavhane & Yadav, 2012). P-glycoprotein also contributes to first pass metabolism of compounds in small intestine. It works synergistically with CYP3A whereby it transfers xenobiotics that escaped metabolic reaction and eliminated from cells into the lumen and bring them back to metabolic exposure (Gavhane & Yadav, 2012). Phase II metabolism involves conjugation of xenobiotics and xenobiotics metabolites which assist the process of excretion of the compounds (Kaminsky & Zhang, 2003). Glutathione S-Transferase is one of the enzyme that play an important role in detoxification and elimination of xenobiotics (Kaminsky & Zhang, 2003). It aids detoxification of xenobiotics by act as receptor for induction of cytochrome P-450 (Hanson-Painton, Griffin & Tang, 1983). Besides, UDP-Glucuronosyltransferases and sulfotransferases also play an important role during phase II metabolism by glucuronidation and sulfation reaction. These reactions increase lipophilic compounds ability to be excreted by increasing their water solubility (Lin, et al., 1999). Therefore, the xenobiotics are readily to be excreted.
Concentration of xenobiotics affects the biotransformation rate and intrinsic clearance. As the drug concentration is higher, intrinsic clearance rate will be lower. At high concentration of xenobiotics such as drug, the first pass metabolism is expected to be lower (Lin, et al., 1999).
References
Bowen, R. (2006). Overview of Transport Across the Intestinal Epithelium. Retrieved November 14, 2016, from http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/transport.html
Dobson, P. D. & Kell, D. B. (2008). Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nature Reviews Drug Discovery, 7, 205-220.
Gavhane, Y. N. & Yadav, A.V. (2012). Loss of orally administered drugs in GI tract. Saudi Pharmaceutical Journal, 20, 331-344.
Hanson-Painton, O., Griffin, M. J., Tang, J. (1983). Involvement of a cytosolic carrier protein in the microsomal metabolism of benzo[a]pyrene in rat liver. Cancer Research, 43, 4198-4206.
Hiraoka, H., Yamamoto, K., Miyoshi, S., Morita, T., Nakamura, K., Kadoi, Y., et al. (2005). Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain. British Journal of Clinical Pharmacology, 60(2), 176–182.
Kaminsky, L. S. & Zhang, Q. Y. (2003). The Small Intestine as A Xenobiotic-Metabolizing Organ. Drug Metabolism And Disposition, 31(12), 1520-1525.
Lin, J. H., Chiba, M. & Baillie, T. A. (1999). Is the Role of the Small Intestine in First-Pass Metabolism Overemphasized? Pharmacological Reviews, 51(2), 137-157.
Meunier, V., Bourrie, M., Berger, Y. & Fabre, G. (1995). The human intestinal epithelial cell line Caco-2; pharmacological and pharmacokinetic applications. Cell Biology and Toxicology, 11, 187-194.
Propofol mechanism of action (n.d.). Retrieved November 18, 2016, from https://www.openanesthesia.org/propofol_mechanism_of_action/
The Digestive System (n.d.). Retrieved November 13, 2016, from http://classes.midlandstech.edu/carterp/Courses/bio211/chap23/chap23.htm
Thorn, H. A. (2012). First-pass Intestinal Metabolism of Drugs: Experiences from in vitro, in vivo and simulation studies (degree of Doctor of Philosophy). Retrieved November 13, 2016, from https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0ahUKEwj57eCyh6bQAhXDo48KHXzmB5IQFggbMAA&url=https%3A%2F%2Fwww.diva-portal.org%2Fsmash%2Fget%2Fdiva2%3A474024%2FFULLTEXT01.pdf&usg=AFQjCNGq8Vu-k_AagOBTty_A06RMFj2GOw&sig2=6aS6Fmy-vCt3zxG_oJM7rw
Yee, S. (1997). In vitro Permeability Across Caco-2 Cells (Colonic) Can Predict In vivo (Small intestinal) Absorption in Man – Fact or Myth. Pharmaceutical Research, 14(6), 763-766.